# The role of sex in the life cycle of Pneumocystis

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2021 · —

## Abstract

Pneumocystis spp. are obligate fungal pathogens that cause a fatal pneumonia (PCP) in
immunocompromised hosts. Few drugs are effective against PCP and there have been no new therapies for its
treatment in decades. Typically, PCP has been associated with patients infected with HIV, however, the fulminate
pneumonia, PCP, and colonization with Pneumocystis jirovecii (the species infecting humans) are emerging
clinical problems in newly susceptible populations in the general and veterans’ populations including bone
marrow recipients; patients receiving chronic immunotherapy for rheumatoid arthritis and other chronic
inflammatory diseases; and cancer chemo- and immunotherapies. The life cycle of Pneumocystis is suggested
to contain both an asexual replication cycle and a sexual cycle involving mating with subsequent formation of
asci containing 8 ascospores (1). During the previous Merit Review, we showed that echinocandin treatment of
rodents infected with P. murina and P. carinii, which target β-1,3-D-glucan synthesis (BG), depleted the asci
which contain BG but large numbers of non-BG expressing life cycle stages remained in the lungs and were
unable to proliferate. We further demonstrated that anidulafungin and caspofungin could prevent infection in a
prophylactic model, suggesting that formation of asci via the sexual cycle may be required for a productive
infection (2). Analysis of gene expression profiles of P. murina in mice treated with anidulafungin, showed strong
upregulation of genes associated with sexual replication, though the resulting infections were devoid of asci, the
product of sexual reproduction, suggesting that P. murina attempted to undergo sexual replication, but could not
due to a lack of BG. Based on these data, we posit that asci, and thus sexual replication, is required to facilitate
progression through the life cycle leading to a productive infection. We further posit that presence of asci is
required for transmission of Pneumocystis infection. In the present proposal, we will explore 2 critical, but
unanswered questions that will lead to a deeper knowledge of the life cycle of Pneumocystis, and also suggest
potential vulnerabilities for targeted treatment concomitant with anidulafungin therapy:
(1) Is sexual replication required for completion of the life cycle of Pneumocystis? Tracking of the
replication status of P. murina during prolonged treatment with anidulafungin by global gene analysis, BG
content, and microscopic methods will reveal whether the non-BG expressing forms numbers remain: 1) static
over time, 2) increase, or 3) decrease; suggesting: 1) the lack of BG blocks replication; 2) that an asexual or
alternative replication phase permits survival of the fungi; or 3) the lack of sexual replication results in elimination
of the infection.
(2) Can sexual replication rebound after cessation of prolonged anidulafungin treatment? Mice will be
treated with anidulafungin for up to 8 weeks, with 2 cessation time point...

## Key facts

- **NIH application ID:** 10047702
- **Project number:** 5I01BX004441-03
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** Melanie T Cushion
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047702

## Citation

> US National Institutes of Health, RePORTER application 10047702, The role of sex in the life cycle of Pneumocystis (5I01BX004441-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047702. Licensed CC0.

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